Mechansims for the propagation of epigenetic states: Role of ATP-dependent chromatin remodelling by SMARCAD1

The genetic material in each cell is packaged and organized by an extremely complex, heterogeneous structure, called chromatin. The basic building block of this structure is called the nucleosome, a molecular protein spool around which DNA winds in almost two turns. Nucleosomes are modified and interact with other proteins to create chromatin structures that shut down genes or allow access to the machinery that read out the information from genes. We will study how nucleosome remodelling and modification enzymes interact to assemble a specific chromatin structure to shut down genes and to stabilise the genome. This research has implications for our understanding of normal development, but also for cancer and fertility.

Chromatin is an incredibly complex, heterogeneous assembly. Specific chromatin structures mediate gene regulation and are required for genome stability and chromosome segregation. Such structures have to be faithfully duplicated for the maintenance of gene expression patterns through development and genome stability. Defects in heterochromatin have been linked to genome instability, infertility, accelerated aging and an enhanced risk of cancer. Despite this fundamental importance, our knowledge how specific chromatin structures, such as heterochromatin, are assembled and maintained through replication is limited.
Our recent research implicates an ATP-dependent remodelling factor, SMARCAD1, in the assembly of heterochromatin during replication. The analysis of chromatin remodelling by SMARCAD1 provides a unique entry point to gain mechanistic insights into how heterochromatin is assembled and what happens if this process is impeded. We use available mice that are deficient in this factor and a combination of cell biology and biochemistry to gain insights into how SMARCAD1 and its binding partners are involved in setting up silenced chromatin during replication. We will test if SMARCAD1 has a role in meiosis through its function in heterochromatin assembly. This research will uncover novel mechanisms into how histone deacetylation, histone ubiquitination, histone variant exchange and nucleosome remodelling are coordinated to propagate condensed chromatin structures.